Steven M. Kawut, MD, MS is a Professor of Medicine and Epidemiology at the University of Pennsylvania School of Medicine (Penn) who has committed his career to the research and care of patients with pulmonary vascular disease (PVD). He heads a federally-funded research program based on the epidemiology and treatment of PVD and right ventricular dysfunction. He has also mentored more than fifty trainees to success in patient-oriented research (POR), resulting in publications and funding and in many cases their own independent academic careers. The candidate's immediate- and long-term career goals during this competitive renewal center on acquiring skills in performing comparative effectiveness research (CER) in rare PVDs and developing his mentorship abilities, specifically in transitioning his funded mentees to independence and in becoming mentors of their own trainees. The environment at Penn is ideal to develop the applicant as a mentor and to foster the academic growth of mentees in these areas. Pulmonary arterial hypertension (PAH) is a rare disease which affects people of all ages, leading to significant morbidity and a high risk of mortality. However, many questions about the study and therapeutic approach to PAH remain unanswered. The minimally important difference (MID) for the six-minute walk distance (6MWD) has not been clearly established in PAH. The use of the 6MWD in early phase studies and as a component of clinical outcomes makes this an important area of research even in the era of long-term studies in PAH. With the proliferation of new therapies for PAH, CER of different treatments in PAH in terms of health-related quality of life and clinical worsening is a major area of interest. Dr. Kawut is involved in two new initiatives which can address these critical questions in PAH and serve as training vehicles for himself and his mentees. First, the FDA has provided Dr. Kawut with individual patient-level data (IPD) from all submitted randomized clinical trials (RCTs) in PAH. Second, Dr. Kawut chairs the Steering Committee of the Pulmonary Hypertension Association Registry (PHAR), which is a prospective registry of newly-diagnosed patients with PAH at Pulmonary Hypertension Care Centers. We aim to derive and validate the MID in the change in 6MWD in PAH and to determine the comparative effectiveness of different drug classes on health-related quality of life and time to clinical worsening in patients with PAH. The long-term goal of this proposal is to refine the conduct of RCTs and clinical care in PAH by validating the MID of the 6MWD and studying the comparative effectiveness of different treatment approaches. These aims provide not only training opportunities for the mentor, but also valuable training and research experiences for mentees at all levels. The opportunities for direct patient involvement in the CER being proposed and direct patient contact make this project ideal for this K24 renewal.